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An intersubunit hydrogen bond in the nicotinic acetylcholine receptor that contributes to channel gating

Gleitsman, Kristin Rule and Kedrowski, Sean M. A. and Lester, Henry A. and Dougherty, Dennis A. (2008) An intersubunit hydrogen bond in the nicotinic acetylcholine receptor that contributes to channel gating. Journal of Biological Chemistry, 283 (51). pp. 35638-35643. ISSN 0021-9258. PMCID PMC2602911. doi:10.1074/jbc.M807226200. https://resolver.caltech.edu/CaltechAUTHORS:GLEjbc08

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Abstract

The muscle nicotinic acetylcholine receptor (nAChR) is a large, allosteric, ligand-gated ion channel with the subunit composition α2βγδ. Though much is now known about the structure of the binding site, relatively little is understood about how the binding event is communicated to the channel gate, causing the pore to open. Here we identify a key hydrogen bond near the binding site that is involved in the gating pathway. Using mutant cycle analysis with the novel unnatural residue α-hydroxyserine (Sah), we find that the backbone N-H of αS191 in loop C makes a hydrogen bond to an anionic side chain of the complementary subunit upon agonist binding. However, the anionic partner is not the glutamate predicted by the crystal structures of the homologous acetylcholine binding protein (AChBP). Instead, the hydrogen bonding partner is the extensively researched aspartate γD174/δD180 -— which had originally been identified as a key binding residue for cationic agonists.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1074/jbc.M807226200DOIArticle
http://www.jbc.org/cgi/content/abstract/283/51/35638PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2602911/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:Copyright 2008 by The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, September 17, 2008, and in revised form, October 21, 2008. This work was supported, in whole or in part, by National Institutes of Health Grants NS 34407 and NS 11756. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The online version of this article (available at http://www.jbc.org) contains supplemental text, a supplemental table, and a supplemental figure. These authors [K.R.G., S.M.A.K.] contributed equally to this work. [K.R.G. was] [p]artially supported by a National Science Foundation graduate research fellowship. [S.M.A.K. was] [p]artially supported by a National Research Service Award training grant.
Funders:
Funding AgencyGrant Number
NIHNS 34407
NIHNS 11756
NSF Graduate Research FellowshipUNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
Issue or Number:51
PubMed Central ID:PMC2602911
DOI:10.1074/jbc.M807226200
Record Number:CaltechAUTHORS:GLEjbc08
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:GLEjbc08
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:12183
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:28 Oct 2008 18:18
Last Modified:08 Nov 2021 22:26

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